The invention is directed to a new, improved process for the production of 1,2-dithiolane-3-pentanoic acid (thioctic acid, .alpha.-lipoic acid). Thioctic acid was produced for the first time in crystalline form from liver extract in 1953 by the American biochemist L. J. Reed and J. C. Gunsalus. The optically active (+)-.alpha.-lipoic acid is a natural material which occurs in slight concentration in animals as well as in the humans. Lipoic acid acts as one of several coenzymes in the oxidative decarboxylation of pyruvate and other .alpha.-ketocarboxylic acids. It belongs to the materials which favorably influence the parenchyma damage of the liver (necotropic materials). D,L-thioctic acid is employed as a pharmaceutical preparative for the treatment of acute and chronic liver illnesses as well as poisonings. In the treatment of illnesses which require a high dosage of chemotherapy which heavily burden the liver, thioctic acid supports the regeneration of the liver. A further area of use for thioctic acid is in the treatment of neuropathy.
There are several multi-step syntheses known for the production of thioctic acid, which are described for example in Acker U.S. Pat. No. 2,752,373; Acker U.S. Pat. No. 2,752,374; Acker U.S. Pat. No. 2,792,406; Reed U.S. Pat. No. 2,980,716; Reed U.S. Pat. No. 3,049,549; and Ose U.S. Pat. No. 3,223,712. Most of the known syntheses for thioctic acid are based on the reaction of 5-chloro-carbonylvaleric acid methyl ester (1) with ethylene (2) in the presence of aluminum chloride. The 8-chloro-6-oxo-octanoic acid methyl ester (3) formed thereby is then converted in various way into thioctic acid. ##STR7##
The synthesis of L. J. Reed and C. J. Nui in J. Amer. Chem. Soc., Volume 77, pages 416-419 (1955) starting from the intermediate step (3) using very corrosive phosphorus tribromide leads to thioctic acid with a modest total yield of 17% based on the acid chloride (1). Starting from the acid chloride (1) according to Reed U.S. Pat. No. 2,980,716 there is obtained a better total yield through a multi-step process, clearly the industrial realizability of this synthesis is limited because of the large number of vacuum distillations necessary. A further synthesis of thioctic acid is described by M. W. Bullock et al in J. Amer. Chem. Soc., Volume 79, pages 1978-1982 (1957) starting from the 8-chloro-6-oxo-octanoic acid methyl ester (3) via the introduction of the sulfur atom into the molecule by means of a special cobalt polysulfide catalyst and hydrogen sulfide. This method of synthesis is not interesting industrially since the catalyst cannot be completely regenerated and besides it is necessary to operate at quite high pressures.
In Acker U.S. Pat. No. 2,792,406 there is described the production of thioctic acid by the reaction of 6,8-dichloro-octanoic acid esters with sodium sulfide and sulfur. Hereby first the chlorine is exchanged with disodium disulfide formed from sodium sulfide and sulfur, acidified. A significant disadvantage of this process is the formation of polymeric thioctic acid which can only be separated with difficulty and only incompletely so that there is a pure thioctic acid obtained only in low yield. The entire disclosures of the patents and two literature articles mentioned above are hereby incorporated by reference and relied upon.
In spite of the numerous known syntheses for thioctic acid there is a need for an economical synthesis with a high yield. The present invention is directed to a process for the production of thioctic acid from readily available starting materials which are reacted in simple chemical operations without drastic conditions. The synthesis shows a very good yield of 47% of theory via 8 steps.